Optimal digestion and absorption of fat depend on regulated presentation of this nutrient to the absorptive sites of the small intestine. Intestinal transit is inhibited by fat in a load-dependent fashion to provide this controlled nutrient delivery whether the region of exposure to fat is limited to the proximal gut (jejunal brake) or extended to the distal gut (ileal brake). In order for the small bowel to respond appropriately to the fat entered, the presence of fat in the lumen must be detected. Afferent nerves that fire specifically in response to luminal fat (fat chemoreceptors) have been found in the lamina propria. Since the terminal ends of these nerves are not in contact with the lumen, a gut endocrine cell in contact with the lumen may serve as a "taste bud" for the small intestine and act on the afferent pathways by releasing a peptide product. Our preliminary data showed that PYY, a peptide that inhibits intestinal transit, is the preabsorptive signal transducer and chylomicron (or its apoprotein component, apo A-IV) is the postabsorptive signal transducer. Since PYY cells are principally found in the distal gut, PYY may be released by fat in the proximal gut via a neurally dependent, CCK-stimulated release mechanism (jejunal brake) but fat in the distal gut may release PYY via a neurally independent, non CCK-stimulated mechanism (ileal brake). In Phase I of the project, we will examine the effect of fat load, the region of fat exposure (proximal vs. distal gut) and the hypothesized mediators on intestinal transit and the release of PYY. In Phase II of the project, we will further examine the conditions for PYY release in a short term culture of ileal PYY cells. This proposal will provide the fundamental physiologic as well as mechanistic information to explain the control of intestinal transit by luminal fat. Such information is needed to develop novel, nutrient-based treatments for patients who are symptomatic from rapid transit including those with dumping syndrome, short bowel syndrome, postvagotomy diarrhea, enteral feeding related diarrhea, gastrectomy, or ileo-anal anastomosis.